1,25-dihydroxy, 20-cyclopropyl,26-27-deuteroalkyl vitamin d3 compounds and methods of use thereof

Abstract

The invention provides vitamin D 3 analogs of cholecalciferol, substituted at carbons-26 and 27 with deuterated alkyl groups, e.g., trideuteromethyl, wherein carbon-16 is a single or double bond, and carbon-23 is a single, double, or triple bond. The invention provides pharmaceutically acceptable esters, salts, and prodrugs thereof. Methods for using the compounds to treat vitamin D 3 associated states, and pharmaceutical compositions containing the compounds are also disclosed.

1 . A vitamin D 3  compound of formula I: 
     
       
         
         
             
             
         
       
     
     wherein:
 A is single or double bond; 
 B is a single, double, or triple bond; 
 X is H 2  or CH 2 ; 
 Y is hydroxyl, OC(O)C 1 -C 4  alkyl, OC(O)hydroxyalkyl, OC(O)haloalkyl; or halogen; 
 Z is hydroxyl, OC(O)C 1 -C 4  alkyl, OC(O)hydroxyalkyl, or OC(O)haloalkyl; and 
 pharmaceutically acceptable esters, salts, and prodrugs thereof. 
 
   
   
       2 . The compound of  claim 1 , wherein Y is hydroxyl. 
   
   
       3 . The compound of  claim 1 , wherein Y is halogen. 
   
   
       4 . The compound of  claim 3 , wherein Y is F. 
   
   
       5 . The compound of  claim 1 , wherein Y is OC(O)C 1 -C 4  alkyl. 
   
   
       6 . The compound of  claim 5 , wherein Y is OC(O)CH 3 . 
   
   
       7 . The compound of  claim 1 , wherein Z is hydroxyl. 
   
   
       8 . The compound of  claim 1 , wherein A is a single bond. 
   
   
       9 . The compound of  claim 1 , wherein A is a double bond. 
   
   
       10 . The compound of  claim 1 , wherein B is a single bond. 
   
   
       11 . The compound of  claim 1 , wherein B is a double bond. 
   
   
       12 . The compound of  claim 1 , wherein B is a triple bond. 
   
   
       13 . The compound of  claim 1 , wherein X is CH 2 . 
   
   
       14 . The compound of  claim 1 , wherein X is H 2 . 
   
   
       15 . The compound of  claim 1 , wherein said compound is 1,25-Dihydroxy-20-cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       16 . The compound of  claim 1 , wherein said compound is 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       17 . The compound of  claim 1 , wherein said compound is 1,25-Dihydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 1 , wherein said compound is 1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       19 . The compound of  claim 1 , wherein said compound is 1α-Fluoro-25-hydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       20 . The compound of  claim 1 , wherein said compound is 3-O-acetyl-1α-fluoro-25-hydroxy-20-cyclopropyl-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       21 . The compound of  claim 1 , wherein said compound is 1,25-Dihydroxy-16-ene-20 cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       22 . The compound of  claim 1 , wherein said compound is 1,25-Dihydroxy-16-ene-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       23 . The compound of  claim 1 , wherein said compound is 1α-Fluoro-25-hydroxy-16-ene-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       24 . A method for treating a subject for a vitamin D 3  associated state, comprising administering to a subject in need thereof an effective amount of a vitamin D 3  compound of  claim 1 , such that said subject is treated for said vitamin D 3  associated state. 
   
   
       25 . (canceled) 
   
   
       26 . The method of  claim 24 , further comprising identifying a subject in need of treatment for a vitamin D 3  associated state. 
   
   
       27 . The method of  claim 24 , wherein said vitamin D 3  associated state is disorder selected from the group consisting of an ILT3-associated disorder, a disorder characterized by an aberrant activity of a vitamin D 3 -responsive cell. 
   
   
       28 . The method of  claim 27 , wherein said ILT3-associated disorder is an immune disorder or an autoimmune disorder. 
   
   
       29 . The method of  claim 28 , wherein said immune disorder is an autoimmune disorder selected from the group consisting of type 1 insulin-dependent diabetes mellitus, adult respiratory distress syndrome, inflammatory bowel disease, dermatitis, meningitis, thrombotic thrombocytopenic purpura, Sjogren's syndrome, encephalitis, uveitis, uveoretinitis, leukocyte adhesion deficiency, rheumatoid arthritis, rheumatic fever, Reiter's syndrome, psoriatic arthritis, progressive systemic sclerosis, primary biliary cirrhosis, pemphigus, pemphigoid, necrotizing vasculitis, myasthenia gravis multiple sclerosis, lupus erythematosus, polymyositis, sarcoidosis, granulomatosis, vasculitis, pernicious anemia, CNS inflammatory disorder, antigen-antibody complex mediated diseases, autoimmune haemolytic anemia, Hashimoto's thyroiditis, Graves disease, habitual spontaneous abortions, Reynard's syndrome, glomerulonephritis, dermatomyositis, chronic active hepatitis, celiac disease, autoimmune complications of AIDS, atrophic gastritis, ankylosing spondylitis and Addison's disease. 
   
   
       30 - 32 . (canceled) 
   
   
       33 . The method of  claim 24 , wherein said disorder characterized by an aberrant activity of a vitamin D 3 -responsive cell is selected from the group consisting of a disorder characterized by an aberrant activity of a hyperproliferative skin cell, a disorder characterized by an aberrant activity of an endocrine cell, a disorder characterized by an aberrant activity of a bone cell, a disorder characterized by an aberrant activity of a vitamin D 3 -responsive smooth muscle cell cirrhosis or chronic renal disease, hypertension, benign prostate hypertrophy, neoplastic disease, neuronal loss, uveitis, interstitial cystitis. 
   
   
       34 . (canceled) 
   
   
       35 . The method of  claim 33 , wherein said disorder characterized by an aberrant activity of a hyperproliferative skin cell is selected from the group consisting of psoriasis, basal cell carcinoma and keratosis. 
   
   
       36 . (canceled) 
   
   
       37 . (canceled) 
   
   
       38 . The method of  claim 33 , wherein said disorder characterized by an aberrant activity of an endocrine cell is secondary hyperparathyroidism. 
   
   
       39 . (canceled) 
   
   
       40 . (canceled) 
   
   
       41 . The method of  claim 33 , wherein said disorder characterized by an aberrant activity of a bone cell is selected from the group consisting of osteoporosis, osteodystrophy, senile osteoporosis, osteomalacia, rickets, osteitis fibrosa cystica, and renal osteodystrophy. 
   
   
       42 - 45 . (canceled) 
   
   
       46 . The method of  claim 33 , wherein said disorder is hypertension and the compound is 1,25-Dihydroxy-20-cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1,25-Dihydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1,3-Di-O-acetyl-1,25-dihydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1α-Fluoro-25-hydroxy-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     3-O-acetyl-1α-fluoro-25-hydroxy-20-cyclopropyl-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1,25-Dihydroxy-16-ene-20 cyclopropyl-26,27-hexadeutero-19-nor-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1,25-Dihydroxy-16-ene-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
     1α-Fluoro-25-hydroxy-16-ene-20-cyclopropyl-26,27-hexadeutero-cholecalciferol: 
     
       
         
         
             
             
         
       
     
   
   
       47 - 56 . (canceled) 
   
   
       57 . The method of  claim 33 , wherein the neoplastic disease is selected from the group consisting of leukemia, lymphoma, melanoma, osteosarcoma, colon cancer, rectal cancer, prostate cancer, bladder cancer, and malignant tumors of the lung, breast, gastrointestinal tract, and genitourinary tract. 
   
   
       58 . (canceled) 
   
   
       59 . (canceled) 
   
   
       60 . The method of  claim 33 , wherein the disorder comprises neuronal loss and is selected from the group consisting of Alzheimer's Disease, Pick's Disease, Parkinson's Disease, Vascular Disease, Huntington's Disease, and Age-Associated Memory Impairment. 
   
   
       61 - 63 . (canceled) 
   
   
       64 . The method of  claim 33 , wherein the disorder is characterized by an aberrant activity of a vitamin D 3 -responsive smooth muscle cell and is selected from the group consisting of uterine myomas, hyperproliferative vascular disease and arterial hypertension. 
   
   
       65 . (canceled) 
   
   
       66 . (canceled) 
   
   
       67 . A method of ameliorating a deregulation of calcium and phosphate metabolism, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 1 , so as to ameliorate the deregulation of the calcium and phosphate metabolism in said subject. 
   
   
       68 . (canceled) 
   
   
       69 . A method of modulating the expression of an immunoglobulin-like transcript 3 (ILT3) surface molecule in a cell, comprising contacting said cell with a compound of  claim 1 , in an amount effective to modulate the expression of an immunoglobulin-like transcript 3 (ILT3) surface molecule in said cell. 
   
   
       70 . (canceled) 
   
   
       71 . A method of treating an ILT3-associated disorder in a subject, comprising administering to a subject in need thereof a compound of  claim 1 , in an amount effective to modulate the expression of an ILT3 surface molecule, thereby treating said ILT3-associated disorder in said subject. 
   
   
       72 - 74 . (canceled) 
   
   
       75 . A method of inducing immunological tolerance in a subject, comprising administering to a subject in need thereof a compound of  claim 1 , in an amount effective to modulate the expression of an ILT3 surface molecule, thereby inducing immunological tolerance in said subject. 
   
   
       76 . (canceled) 
   
   
       77 . (canceled) 
   
   
       78 . A method of inhibiting transplant rejection in a subject comprising administering to a subject in need thereof a compound  claim 1 , in an amount effective to modulate the expression of an ILT3 surface molecule, thereby inhibiting transplant rejection in said subject. 
   
   
       79 - 81 . (canceled) 
   
   
       82 . A method for modulating immunosuppressive activity by an antigen-presenting cell, comprising contacting an antigen-presenting cell with a compound of  claim 1 , in an amount effective to modulate ILT3 surface molecule expression, thereby modulating said immunosuppressive activity by said antigen-presenting cell. 
   
   
       83 . (canceled) 
   
   
       84 . A method for preventing or treating bladder dysfunction in a subject comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 , thereby to prevent or treat bladder dysfunction in said subject. 
   
   
       85 - 95 . (canceled) 
   
   
       96 . The method of  claim 24 , wherein the subject is a mammal. 
   
   
       97 . The method of  claim 96 , wherein the subject is human. 
   
   
       98 . The method of  claim 24 , wherein said compound is administered orally, intravenously, topically or parenterally. 
   
   
       99 - 101 . (canceled) 
   
   
       102 . The method of  claim 24 , wherein said compound is administered at a concentration of 0.001 μg-100 μg/kg of body weight. 
   
   
       103 . A pharmaceutical composition, comprising a compound of any one of  claim 1 , and a pharmaceutically acceptable diluent or carrier. 
   
   
       104 . The pharmaceutical composition of  claim 103 , wherein said compound is present in an amount effective to treat a vitamin D 3  associated state. 
   
   
       105 - 108 . (canceled) 
   
   
       109 . A packaged formulation for use in the treatment of a vitamin D 3  associated state, comprising a pharmaceutical composition comprising a compound of  claim 1 , and instructions for use in the treatment of a vitamin D 3  associated state. 
   
   
       110 - 112 . (canceled)